Hypotensive agents



2,858,312 Patented Oct. 28, 1958 HYPOTENSIV E AGENTS Stephen M. Olin,Elkhart, Ind., assignor to Miles Laboratories, Inc., Elkhart, Ind., acorporation of Indiana No Drawing. Application February 17, 1956 SerialNo. 566,072

Claims. (Cl. 260-268) This invention relates to compounds possessingimportant physiological activity as hypotensives and is acontinuation-in-part of my earlier filed copendingpatent applicationSerial No. 462,123, filed Ocober 13, 1954, and since abandoned.

More particularly, the invention relates to 1,4-unsymmetricallysubstituted piperazines derivatives having the following empiricalformula:

wherein R is selected from the group consisting of lower alkylcontaining 4 to 8 carbon atoms, furfuryl and cyclohexyl, and Xrepresents alkoxyl groups, or hydroxyl groups which may be attached toany two of the carbons on the phenyl ring, as for example at the 3,4 or2,3 positions and Y represents a lower alkyl. In addition to the freebases of these compounds, the acid addition salts such as the sulfate,the hydrochloride or hydrobromide and like salts of these compounds arealso within the specific contemplation of this invention.

That reaction found to be productive of good yields of the claimedcompounds involves the interaction of the appropriateN,N-bis(2-haloalkyl) tertiary amine with the appropriate primary amineas represented in the following:

X CHzCHzCl X Y OHzCHgOI CHgCHzOH This compound is prepared in excellentyield by the addition of ethylene oxide to an aqueous suspension of thea alkylphenylethylamine. To this primary amine (1.0 mole) and 50 ml. ofwater at 5060 C., ethylene oxide (2.2 moles) was passed in or addeddropwise to the batch. At the end of the addition, the reaction mixturewas distilled.

With the X substituent in the foregoing formula representing a methoxysubstituent in the 3,4 positions and Y a methyl substituent, a 50% yieldof a product having a boiling point of 170-l73/.15 mm. and 21 1) 1.540was obtained. This compoundhas a theoretical nitrogen content of 4.93%and by electrometric titration with was found to be perchloric acid indioxane a product of 4.94% Was found.

On treatment with thionyl chloride, the hydroxyl groups in the twobis-hydroxyalkylamines are replaced by chlorine to give theN,N-bis(2-chloroalkyl) tertiary amines shown.

nitrogen content for the X GHzCHzCl X Y CHzCHnCl To a solution of theN,N-bis(2-hydroxyethyl) tertiary amine 1.0 moles) in 400 ml. ofchloroform is added thionyl chloride (2.2 moles). The reaction mixtureis refluxed until the evolution of gas abated and the mixture thenconcentrated under reduced pressure. The residual hydrochloride is theneither recrystallized without further treatment or converted to the freebase by cold concentrated sodium hydroxide and extracted with toluene orxylene. However, this bis-chloro compound more conveniently handled andstored as the hydrochloride salt.

With X representing methoxy substituents in the 3,4 positions and Y amethyl substituent in the above formula, a yield of was obtained withthe salt having a melting point of 146148 employing isopropanol as thecrystallizing solvent. Calculated chlorine content for the compound is9.94% and that found by electrometric titration in water was 9.91%.

Returning to the final reaction first described, a mixture of theselected N,N-bis(2- chloroethyl) amine or its hydrochloride salt asprepared above is reacted With the selected primary amine to achieve thecyclization resulting in the piperazine ring. The reaction proceeds withor without solvent at temperatures in the range of 80 to 190.

In line with the foregoing, the following examples provide a descriptionof the specific operations performed under the general methodsdescribed.

EXAMPLE I I [2-(3,4-dimethoxyphenyl) -1-methylethyl]-4-furfurylpiperazine 17.8 g. (0.05 mole)N,N-bis-(2-chloroethyl)-2-(3,4-

dimethoxyphenyl)-l-methylethylamine hydrochloride and 19.4 g. (0.20mole) furfurylamine were placed in a ml. round-bottomed flask fittedstirrer and thermometer. The reaction mixture was stirred and aspontaneous reaction began, upon which reaction the temperature rose toAfter the initial reaction was over and the temperature began to fall,external heat was applied to maintain the reaction mixture at 110-l20for thirty minutes. The reaction mixture was dissolved in 50 ml. ofwater and 50 ml. of ethyl acetate. The ethyl acetate layer was separatedand the aqueous layer was extracted with a 25 ml. portion of ethylacetate. The combined organic layers were dried and concentrated. Theresidue was distilled under reduced pressure. 10.5 g. of1[2-(3,4-dimethoxyphenyl)- l-methylethyl]-4-furfuryl-piperazine (61%yield) as obtained by this reaction had a boiling point of l71-l8l at0.075 mm. and refractive index n D 1.552.

The free base (10.5 g., 0.061 mole) in 100 ml. of ether was combinedwith an excess of etheral hydrogen chloride. The resulting precipitatewas recrystallized from 50 ml. of methanol and ml. of water. The yieldobtained from this reaction was 10.3 g. having a melting point of286-288. the dihydrochloride for the product.

with a reflux condenser,

Thepercent chlorine calculated for} is 16.99 as compared to 16.74 found3 EXAMPLE II 1-(2-methylpr0pyl)-4-[2-(3,4-dimethoxyphenyl)-1-methylethyl] piperazine 190 g. (0.26' mole) iso-butylamineand a toluenesolution of N,N-bis-(2-chloroethyl) -2-.(3,4-dimethoxyphenyl)l-methylethylamine were placed in a 250 ml. roundbottomed flask fittedwith a reflux condenser, stirrer and thermometen The reaction mixturewas heated under reflux for three hours, cooled and combined with sodiumhydroxide (12.0 g., 0.3 mole) in 50 ml. of water. The toluene layer wasseparated, washed with water, dried and concentrated. The residue wasdistilled under reduced pressure. The. result of this reaction was 23.6g. 1 (2- methylpropyl) 4- l-methylethyllpiperazine (82% yield), having aboiling point of 145-151 at 0.12 mm. and refractive index n 1.529. Uponredistillation 16.5 g. was yielded having a boiling point of 147151at0.2 mm. and refractive index n 1.527.

17.8 g. (0.056 mole) free base in 25 ml. methanol was added to a coldsolution of hydrogen chloride (5.0 g., 0.13 mole) in 60 ml. ether. Theresulting precipitate was washed with ether and dried. This resulted ina yield of 20.0 g. having a melting point of 286287. The percent.chlorine calculated for the dihydrochloride is 18.03 as compared with17.75 found for the product.

The following is. illustrative of a very satisfactory method ofintroducing hydroxyl substituents on the phenyl moiety by dealkylationof alkoxy substituents.

EXAMPLE III l-(Z-methylpropyl) -4- [2-(3,4-dihydroxyphenyl) -1-methylethyl] -piperazine 15.0 g. (0.04 mole)1-(2-methylpropyl)-4-[2-(3,4-dimethoxyphenyl)-l-methylethyl] piperazinedihydrochloride and 100 ml. of redistilled 48% hydrobromic acid wereplaced in a 250 ml. round-bottomed flask fitted with a reflux condenser.The reaction mixture was heated to reflux and glacial acetic acid ml.)was added to suppress foaming. The reaction mixture was refluxed forthree hours. The acidic solvents were removed under reduced pressure andthe residue was neutralized with 5% sodium carbonate to pH 9.0. Theresulting suspension was extracted with three portions of ether (200 ml.total). The dried'ethereal solution was combined with an excess ofethereal hydrogen chloride and the resulting precipitate: wasrecrystallized from 100 ml. ethanol and ml. water; The result of thisreaction was a yield of 9.5 g. having a melting point of 299-301". Thepercent chlorine calculated for the dihydrochloride is 19.41 as comparedto 19.19 found for the product.

The following is illustrative of a very satisfactory method of preparingmethoxy derivatives having the for- 1 mole of the bis-chloroethylamine,5 moles of the appropriate primary amine and 1 liter of xylene wereplaced in a three liter three-necked flask fitted with a thermometer,stirrer and reflux condenser and the reaction mixture heated underreflux for four hours. The reaction mixture was then cooled and 200 ml.of cold; aqueous sodiumhydroxide (30%) was added thereto. The xylenelayer. wasremoved and dried. The xylene was removed by distillation andthe residue dissolved in alcohol; or ether and combined with etherealhydrogen chloride. -The resulting salt was recrystallized in anappropriate solvent until the correct analysis was obtained on ovendried material.

[2 (3,4 dirnethoxyphenyD- Compounds possessing said formula and producedby the above method included those wherein R was as indicated in thefollowing table and which were crystallized in the solvent and had themelting point and chlorine analysis therein indicated:

TABLE A Chlorine Analysis M. P. of Orystallizing R Salt, Solvent degreesPercent Percent calculated foun isoamyl 17. 41 17.25 ethanol. 16. 75 16.70 Isopropanol. 2-heptyl 16. 28 16. 24 Ethanol-ethyl acetate. Z-pentyl261-263 17.41 17.25 Ethyl acetate. 1,1,3, 3-tetra-methyl- 250-252 15.7815. 64 Methanol-ethyl uty acetate. 1-methy1-2-(3,4-dt- 274-275 13. 7613. 83 Ethanol-acetone.

methoxyphenethyl. Isomer of above 284-282 13. 76 13.89 Methanol-water.

(higher melting free base). 1,1-di thyl propyL--- 260-262 15.91 15.62Methanol-ethyl acetate.

The following is illustrative of a very satisfactory method of preparinghydroxy derivatives having the for-- mula:

01124311 HO-O-oHZOH-N N-R g 11 \zm-ofll EXAMPLE V In a one liter flask.fitted with a reflux condenser were placed 0.1 mole of the methoxyderivative of Example TV and 150 ml. of hy-drobromic acid (48%). Thereaction mixture was heated to reflux. Sufl'lcient glacial acetic acid(ca. 25 ml.) was added to reduce foaming and to dissolve the compound.Refluxing was then continued for two to five hours.

was recrystallized from. water-alcohol mixtures. Someof the resultingsalts required four hours at to remove water of crystallization.

Compounds produced by theabove method include, 1 those wherein R was asindicated in the following table:

They were crystallized in the solvent and had the melting point andanalysis indicated in the table.

The free base was isolated and converted to a hydrochloride by a,procedure analogous to Example III.

In addition to the above named compounds, the following have also beenproduced by the general methods outlined in said Examples IV and V:1-[l-ethyl-2-(2,3-

dimethoxyphenyl)ethyl] -4- niethyl propyl piperazine which as thedihydrochloride salt melted at 252-254. Its percent nitrogen calculatedfor C H Cl N O was. 6.88% as compared with 6.78% found for the product.

Demethylation of the corresponding methyl analog of After cooling, thecold reaction mixture was filtered to remove theproduct-which was 56.96%While that found was 56.73%. More stringent treatment gave the fullymethylated product 1-[2- (2,3-hydroxylphenyl)-1-methyl ethyll-4-methylpropyl piperazine and which as the dihydrobromide monohydrate saltmelted at 281282. 33.93% bromine was found as compared to a 33.80%bromine content cal- Culated for CnHgoBI'zNzOzHzO.

Other compounds produced were 1-[2(3,4-methoxy phenyl)-1-ethylethyll-4-methyl propyl piperazine which as the clihydrochloride saltmelted at 265266 and 1-[2- (3,4-dimethoxyphenyl)-1-methyl ethyl] 4 (3hydroxyphenyl) piperazine which also as the dihydrochloride salt meltedat 244-246". Also produced by said method of Example V was 1 [2 (3,4dihydroxyphenyl) 1 ethyl ethyl] -4 methyl butyl piperazine which as thedihydromide monohydrate salt melted at 240-242" and was soluble in waterand alcohol. Calculated for C H Br N O H O its Br content would be32.86%, its N 5.76% which compared with that found Br 32.41% and N5.81%.

Ordinarily it was found convenient to isolate the meth oxy compounds ashydrochlorides and the hydroxy com pounds as hydrobromides.

These compounds in either the free base forms or as the salts can beconveniently employed in combination with the well-known pharmaceuticalexcipients such as elixirs or conventional tabletting compositions, forexample.

The salts of the free bases are obtainable in the form of various acidaddition salts such as exemplified by the dihydrochlorides,dihydrobromide monohydrates, and the sulfates. The most satisfactoryyields of the dihydrochloride, without undue development of themonohydrochloride, were obtained by adding a slight excess of a solutionof anhydrous hydrogen chloride to a solution of the free base in solventwhich would allow the salt to crystallize slowly and completely.Similarly, there is a problem arising from the hemisulfates in thepreparation of the sulfates. However, the hemisulfates wereintentionally prepared in an eflort to produce a salt less acidic thanthe aqueous solutions of the sulfates and dihydrochlorides whichexhibited a pH of 1 to 3. The hemisulfates in solution had a pH of from3 to 3.5 which solutions could be adjusted to a slightly higher pHbefore the free base began to precipitate.

What is claimed is:

1. A member of the having the formula:

group consisting of compounds and acid addition salts thereof wherein Ris selected from the group consisting of lower alkyl containing 4 to 8carbon atoms, l-lower alkyl-2-[3,4-di-(lower alkoxy)] phenethyl, l-loweralkyl-2-(3,4-dihydroxy) phenethyl, furfuryl and cyclohexyl, X isselected from the group consisting of lower alkoxy and hydroxy, and Y islower alkyl.

2. 1-(2-methylpropyl)-4-[2-(3,4 dimethoxyphenyD-lmethylethyl]piperazine.

3. 1-[2-(3,4-dimethoxyphenyl)-1-methylethyl] 4- furiuryl piperazine.

4. 1-(Z-methylpropyl)-4-[2-(3,4 dihydroxyphenyl)-1- methyl ethyl]piperazine.

5. 1-[l-ethyl-Z-(2,3-dimethoxyphenyl) ethyl] 4 methylpropyl piperazine.

6. l- 1-ethyl-2- 3,4-dimethoxyphenyl ethyl] -4-methylpropyl piperazine.

7. A piperazine compound having the formula N-CtH7 OH -OH; wherein eachX represents a hydroxy group and Y is a lower alkyl.

8. A piperazine compound having the formula X CH CH @crwpn-r N-CAHDwherein each X represents a hydroxy group and Y is a lower alkyl.

10. A piperazine compound having the formula wherein each X represents alower alkoxy group and Y is a lower alkyl.

11. A piperazine compound having the formula X /CH2-CHQ X CHPC 1 whereineach X represents a hydroxy group and Y is a lower alkyl.

12. A piperazine compound having the formula wherein each X represents alower alkoxy group and Y is a lower alkyl.

13. A piperazine compound having the formula wherein each X represents alower hydroxy group and Y is a lower alkyl.

14. A piperazine compound having the formula wherein each X represents alower alkoxy group and Y is a lower alkyl.

15. A piperazine compound having the formula OTHER REFERENCES ChemicalAbstracts, vol. 46, page 8661c (1952).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No2,858,312 October 28, 1958 Stephen M, Olin It is hereby certified thaterror appears in the printed specification of the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 6, lines'A. to 7 extreme right==hand portion of the formula, forN G H7" read M=CH9 =u Signed and sealed this 10th day of February 1959,

(SEAL) Attest: I

KARL Ha. AXLINE ROBERT C WATSON Commissioner of Patents AttestingOfficer

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS HAVING THE FORMULA: